Biomolecules

23 pages, 1795 KiB

Open AccessEditor’s ChoiceReview

Overview of Evidence-Based Chemotherapy for Oral Cancer: Focus on Drug Resistance Related to the Epithelial-Mesenchymal Transition

by Jingjing Sha, Yunpeng Bai, Huy Xuan Ngo, Tatsuo Okui and Takahiro Kanno

Biomolecules 2021, 11(6), 893; https://doi.org/10.3390/biom11060893 - 16 Jun 2021

Cited by 48 | Viewed by 5065

Abstract

The increasing incidence of resistance to chemotherapeutic agents has become a major issue in the treatment of oral cancer (OC). Epithelial-mesenchymal transition (EMT) has attracted a great deal of attention in recent years with regard to its relation to the mechanism of chemotherapy [...] Read more.

The increasing incidence of resistance to chemotherapeutic agents has become a major issue in the treatment of oral cancer (OC). Epithelial-mesenchymal transition (EMT) has attracted a great deal of attention in recent years with regard to its relation to the mechanism of chemotherapy drug resistance. EMT-activating transcription factors (EMT-ATFs), such as Snail, TWIST, and ZEB, can activate several different molecular pathways, e.g., PI3K/AKT, NF-κB, and TGF-β. In contrast, the activated oncological signal pathways provide reciprocal feedback that affects the expression of EMT-ATFs, resulting in a peritumoral extracellular environment conducive to cancer cell survival and evasion of the immune system, leading to resistance to multiple chemotherapeutic agents. We present an overview of evidence-based chemotherapy for OC treatment based on the National Comprehensive Cancer Network (NCCN) Chemotherapy Order Templates. We focus on the molecular pathways involved in drug resistance related to the EMT and highlight the signal pathways and transcription factors that may be important for EMT-regulated drug resistance. Rapid progress in antitumor regimens, together with the application of powerful techniques such as high-throughput screening and microRNA technology, will facilitate the development of therapeutic strategies to augment chemotherapy. Full article

(This article belongs to the Special Issue EMT and Cancer)

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11 pages, 574 KiB

Open AccessEditor’s ChoiceReview

Hydrogen Sulfide (H₂S) and Polysulfide (H₂S_n) Signaling: The First 25 Years

by Hideo Kimura

Biomolecules 2021, 11(6), 896; https://doi.org/10.3390/biom11060896 - 16 Jun 2021

Cited by 103 | Viewed by 6365

Abstract

Since the first description of hydrogen sulfide (H₂S) as a toxic gas in 1713 by Bernardino Ramazzini, most studies on H₂S have concentrated on its toxicity. In 1989, Warenycia et al. demonstrated the existence of endogenous H₂S [...] Read more.

Since the first description of hydrogen sulfide (H₂S) as a toxic gas in 1713 by Bernardino Ramazzini, most studies on H₂S have concentrated on its toxicity. In 1989, Warenycia et al. demonstrated the existence of endogenous H₂S in the brain, suggesting that H₂S may have physiological roles. In 1996, we demonstrated that hydrogen sulfide (H₂S) is a potential signaling molecule, which can be produced by cystathionine β-synthase (CBS) to modify neurotransmission in the brain. Subsequently, we showed that H₂S relaxes vascular smooth muscle in synergy with nitric oxide (NO) and that cystathionine γ-lyase (CSE) is another producing enzyme. This study also opened up a new research area of a crosstalk between H₂S and NO. The cytoprotective effect, anti-inflammatory activity, energy formation, and oxygen sensing by H₂S have been subsequently demonstrated. Two additional pathways for the production of H₂S with 3-mercaptopyruvate sulfurtransferase (3MST) from l- and d-cysteine have been identified. We also discovered that hydrogen polysulfides (H₂S_n, n ≥ 2) are potential signaling molecules produced by 3MST. H₂S_n regulate the activity of ion channels and enzymes, as well as even the growth of tumors. S-Sulfuration (S-sulfhydration) proposed by Snyder is the main mechanism for H₂S/H₂S_n underlying regulation of the activity of target proteins. This mini review focuses on the key findings on H₂S/H₂S_n signaling during the first 25 years. Full article

(This article belongs to the Special Issue Hydrogen Sulfide and Polysulfides, Endogenous Mammalian Transmitters——Honorary Special Issue Commemorating the Work of Prof. Hideo Kimura)

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16 pages, 2729 KiB

Open AccessEditor’s ChoiceArticle

A Sesquiterpene Synthase from the Endophytic Fungus Serendipita indica Catalyzes Formation of Viridiflorol

by Fani Ntana, Wajid W. Bhat, Sean R. Johnson, Hans J. L. Jørgensen, David B. Collinge, Birgit Jensen and Björn Hamberger

Biomolecules 2021, 11(6), 898; https://doi.org/10.3390/biom11060898 - 16 Jun 2021

Cited by 22 | Viewed by 5732

Abstract

Interactions between plant-associated fungi and their hosts are characterized by a continuous crosstalk of chemical molecules. Specialized metabolites are often produced during these associations and play important roles in the symbiosis between the plant and the fungus, as well as in the establishment [...] Read more.

Interactions between plant-associated fungi and their hosts are characterized by a continuous crosstalk of chemical molecules. Specialized metabolites are often produced during these associations and play important roles in the symbiosis between the plant and the fungus, as well as in the establishment of additional interactions between the symbionts and other organisms present in the niche. Serendipita indica, a root endophytic fungus from the phylum Basidiomycota, is able to colonize a wide range of plant species, conferring many benefits to its hosts. The genome of S. indica possesses only few genes predicted to be involved in specialized metabolite biosynthesis, including a putative terpenoid synthase gene (SiTPS). In our experimental setup, SiTPS expression was upregulated when the fungus colonized tomato roots compared to its expression in fungal biomass growing on synthetic medium. Heterologous expression of SiTPS in Escherichia coli showed that the produced protein catalyzes the synthesis of a few sesquiterpenoids, with the alcohol viridiflorol being the main product. To investigate the role of SiTPS in the plant-endophyte interaction, an SiTPS-over-expressing mutant line was created and assessed for its ability to colonize tomato roots. Although overexpression of SiTPS did not lead to improved fungal colonization ability, an in vitro growth-inhibition assay showed that viridiflorol has antifungal properties. Addition of viridiflorol to the culture medium inhibited the germination of spores from a phytopathogenic fungus, indicating that SiTPS and its products could provide S. indica with a competitive advantage over other plant-associated fungi during root colonization. Full article

(This article belongs to the Section Chemical Biology)

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25 pages, 9292 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Characterization of Growth and Cell Cycle Events Affected by Light Intensity in the Green Alga Parachlorella kessleri: A New Model for Cell Cycle Research

by Vilém Zachleder, Ivan N. Ivanov, Veronika Kselíková, Vitali Bialevich, Milada Vítová, Shuhei Ota, Tsuyoshi Takeshita, Shigeyuki Kawano and Kateřina Bišová

Biomolecules 2021, 11(6), 891; https://doi.org/10.3390/biom11060891 - 15 Jun 2021

Cited by 15 | Viewed by 4515

Abstract

Multiple fission is a cell cycle variation leading to the production of more than two daughter cells. Here, we used synchronized cultures of the chlorococcal green alga Parachlorella kessleri to study its growth and pattern of cell division under varying light intensities. The [...] Read more.

Multiple fission is a cell cycle variation leading to the production of more than two daughter cells. Here, we used synchronized cultures of the chlorococcal green alga Parachlorella kessleri to study its growth and pattern of cell division under varying light intensities. The time courses of DNA replication, nuclear and cellular division, cell size, total RNA, protein content, dry matter and accumulation of starch were observed at incident light intensities of 110, 250 and 500 µmol photons m⁻²s⁻¹. Furthermore, we studied the effect of deuterated water on Parachlorella kessleri growth and division, to mimic the effect of stress. We describe a novel multiple fission cell cycle pattern characterized by multiple rounds of DNA replication leading to cell polyploidization. Once completed, multiple nuclear divisions were performed with each of them, immediately followed by protoplast fission, terminated by the formation of daughter cells. The multiple fission cell cycle was represented by several consecutive doublings of growth parameters, each leading to the start of a reproductive sequence. The number of growth doublings increased with increasing light intensity and led to division into more daughter cells. This study establishes the baseline for cell cycle research at the molecular level as well as for potential biotechnological applications, particularly directed synthesis of (deuterated) starch and/or neutral lipids as carbon and energy reserves. Full article

(This article belongs to the Special Issue Cell Cycle Regulation of Algae)

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10 pages, 1277 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Towards a Better Understanding of the Relationships between Galectin-7, p53 and MMP-9 during Cancer Progression

by Yves St-Pierre

Biomolecules 2021, 11(6), 879; https://doi.org/10.3390/biom11060879 - 14 Jun 2021

Cited by 12 | Viewed by 4399

Abstract

It has been almost 25 years since the discovery of galectin-7. This member of the galectin family has attracted interest from many working in the cancer field given its highly restricted expression profile in epithelial cells and the fact that cancers of epithelial [...] Read more.

It has been almost 25 years since the discovery of galectin-7. This member of the galectin family has attracted interest from many working in the cancer field given its highly restricted expression profile in epithelial cells and the fact that cancers of epithelial origin (carcinoma) are among the most frequent and deadly cancer subtypes. Initially described as a p53-induced gene and associated with apoptosis, galectin-7 is now recognized as having a protumorigenic role in many cancer types. Several studies have indeed shown that galectin-7 is associated with aggressive behavior of cancer cells and induces expression of MMP-9, a member of the matrix metalloproteinases (MMP) family known to confer invasive behavior to cancer cells. It is therefore not surprising that many studies have examined its relationships with p53 and MMP-9. However, the relationships between galectin-7 and p53 and MMP-9 are not always clear. This is largely because p53 is often mutated in cancer cells and such mutations drastically change its functions and, consequently, its association with galectin-7. In this review, we discuss the functional relationships between galectin-7, p53 and MMP-9 and reconcile some apparently contradictory observations. A better understanding of these relationships will help to develop a working hypothesis and model that will provide the basis for further research in the hope of establishing a new paradigm for tackling the role of galectin-7 in cancer. Full article

(This article belongs to the Special Issue Cell Biology of Galectins)

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15 pages, 21732 KiB

Open AccessEditor’s ChoiceReview

Welcome to the Family: Identification of the NAD⁺ Transporter of Animal Mitochondria as Member of the Solute Carrier Family SLC25

by Mathias Ziegler, Magnus Monné, Andrey Nikiforov, Gennaro Agrimi, Ines Heiland and Ferdinando Palmieri

Biomolecules 2021, 11(6), 880; https://doi.org/10.3390/biom11060880 - 14 Jun 2021

Cited by 22 | Viewed by 7021

Abstract

Subcellular compartmentation is a fundamental property of eukaryotic cells. Communication and metabolic and regulatory interconnectivity between organelles require that solutes can be transported across their surrounding membranes. Indeed, in mammals, there are hundreds of genes encoding solute carriers (SLCs) which mediate the selective [...] Read more.

Subcellular compartmentation is a fundamental property of eukaryotic cells. Communication and metabolic and regulatory interconnectivity between organelles require that solutes can be transported across their surrounding membranes. Indeed, in mammals, there are hundreds of genes encoding solute carriers (SLCs) which mediate the selective transport of molecules such as nucleotides, amino acids, and sugars across biological membranes. Research over many years has identified the localization and preferred substrates of a large variety of SLCs. Of particular interest has been the SLC25 family, which includes carriers embedded in the inner membrane of mitochondria to secure the supply of these organelles with major metabolic intermediates and coenzymes. The substrate specificity of many of these carriers has been established in the past. However, the route by which animal mitochondria are supplied with NAD⁺ had long remained obscure. Only just recently, the existence of a human mitochondrial NAD⁺ carrier was firmly established. With the realization that SLC25A51 (or MCART1) represents the major mitochondrial NAD⁺ carrier in mammals, a long-standing mystery in NAD⁺ biology has been resolved. Here, we summarize the functional importance and structural features of this carrier as well as the key observations leading to its discovery. Full article

(This article belongs to the Special Issue Mitochondrial Transport Proteins)

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24 pages, 1529 KiB

Open AccessEditor’s ChoiceReview

Adipose-Derived Stem Cells Secretome and Its Potential Application in “Stem Cell-Free Therapy”

by Anna Trzyna and Agnieszka Banaś-Ząbczyk

Biomolecules 2021, 11(6), 878; https://doi.org/10.3390/biom11060878 - 13 Jun 2021

Cited by 131 | Viewed by 9932

Abstract

Adipose-derived stem cells (ASCs) secrete many cytokines, proteins, growth factors, and extracellular vesicles with beneficial outcomes that can be used in regenerative medicine. It has great potential, and the development of new treatment strategies using the ASCs secretome is of global interest. Besides [...] Read more.

Adipose-derived stem cells (ASCs) secrete many cytokines, proteins, growth factors, and extracellular vesicles with beneficial outcomes that can be used in regenerative medicine. It has great potential, and the development of new treatment strategies using the ASCs secretome is of global interest. Besides cytokines, proteins, and growth factors, the therapeutic effect of secretome is hidden in non-coding RNAs such as miR-21, miR-24, and miR-26 carried via exosomes secreted by adequate cells. The whole secretome, including ASC-derived exosomes (ASC-exos) has been proven in many studies to have immunomodulatory, proangiogenic, neurotrophic, and epithelization activity and can potentially be used for neurodegenerative, cardiovascular, respiratory, inflammatory, and autoimmune diseases as well as wound healing treatment. Due to limitations in the use of stem cells in cell-based therapy, its secretome with emphasis on exosomes seems to be a reasonable and safer alternative with increased effectiveness and fewer side effects. Moreover, the great advantage of cell-free therapy is the possibility of biobanking the ASCs secretome. In this review, we focus on the current state of knowledge on the use of the ASCs secretome in stem cell-free therapy. Full article

(This article belongs to the Special Issue Recent Advances in Translational Adipose-Derived Stem Cell Biology)

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23 pages, 3286 KiB

Open AccessEditor’s ChoiceReview

Hyperactivated RAGE in Comorbidities as a Risk Factor for Severe COVID-19—The Role of RAGE-RAS Crosstalk

by Sara Chiappalupi, Laura Salvadori, Rosario Donato, Francesca Riuzzi and Guglielmo Sorci

Biomolecules 2021, 11(6), 876; https://doi.org/10.3390/biom11060876 - 12 Jun 2021

Cited by 25 | Viewed by 4905

Abstract

The receptor for advanced glycation-end products (RAGE) is a multiligand receptor with a role in inflammatory and pulmonary pathologies. Hyperactivation of RAGE by its ligands has been reported to sustain inflammation and oxidative stress in common comorbidities of severe COVID-19. RAGE is essential [...] Read more.

The receptor for advanced glycation-end products (RAGE) is a multiligand receptor with a role in inflammatory and pulmonary pathologies. Hyperactivation of RAGE by its ligands has been reported to sustain inflammation and oxidative stress in common comorbidities of severe COVID-19. RAGE is essential to the deleterious effects of the renin–angiotensin system (RAS), which participates in infection and multiorgan injury in COVID-19 patients. Thus, RAGE might be a major player in severe COVID-19, and appears to be a useful therapeutic molecular target in infections by SARS-CoV-2. The role of RAGE gene polymorphisms in predisposing patients to severe COVID-19 is discussed. Full article

(This article belongs to the Collection Feature Papers in Section 'Molecular Medicine')

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18 pages, 3245 KiB

Open AccessEditor’s ChoiceArticle

HK2 Mediated Glycolytic Metabolism in Mouse Photoreceptors Is Not Required to Cause Late Stage Age-Related Macular Degeneration-Like Pathologies

by Shun-Yun Cheng, Anneliese Malachi, Joris Cipi, Shan Ma, Richard S. Brush, Martin-Paul Agbaga and Claudio Punzo

Biomolecules 2021, 11(6), 871; https://doi.org/10.3390/biom11060871 - 11 Jun 2021

Cited by 5 | Viewed by 4987

Abstract

Age-related macular degeneration (AMD) is a multifactorial disease of unclear etiology. We previously proposed that metabolic adaptations in photoreceptors (PRs) play a role in disease progression. We mimicked these metabolic adaptations in mouse PRs through deletion of the tuberous sclerosis complex (TSC) protein [...] Read more.

Age-related macular degeneration (AMD) is a multifactorial disease of unclear etiology. We previously proposed that metabolic adaptations in photoreceptors (PRs) play a role in disease progression. We mimicked these metabolic adaptations in mouse PRs through deletion of the tuberous sclerosis complex (TSC) protein TSC1. Here, we confirm our previous findings by deletion of the other complex protein, namely TSC2, in rod photoreceptors. Similar to deletion of Tsc1, mice with deletion of Tsc2 in rods develop AMD-like pathologies, including accumulation of apolipoproteins, migration of microglia, geographic atrophy, and neovascular pathologies. Subtle differences between the two mouse models, such as a significant increase in microglia activation with loss of Tsc2, were seen as well. To investigate the role of altered glucose metabolism in disease pathogenesis, we generated mice with simulation deletions of Tsc2 and hexokinase-2 (Hk2) in rods. Although retinal lactate levels returned to normal in mice with Tsc2-Hk2 deletion, AMD-like pathologies still developed. The data suggest that the metabolic adaptations in PRs that cause AMD-like pathologies are independent of HK2-mediated aerobic glycolysis. Full article

(This article belongs to the Special Issue Ocular Diseases and Therapeutics)

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16 pages, 3919 KiB

Open AccessEditor’s ChoiceArticle

Bioinstructive Layer-by-Layer-Coated Customizable 3D Printed Perfusable Microchannels Embedded in Photocrosslinkable Hydrogels for Vascular Tissue Engineering

by Cristiana F. V. Sousa, Catarina A. Saraiva, Tiago R. Correia, Tamagno Pesqueira, Sónia G. Patrício, Maria Isabel Rial-Hermida, João Borges and João F. Mano

Biomolecules 2021, 11(6), 863; https://doi.org/10.3390/biom11060863 - 10 Jun 2021

Cited by 34 | Viewed by 5565

Abstract

The development of complex and large 3D vascularized tissue constructs remains the major goal of tissue engineering and regenerative medicine (TERM). To date, several strategies have been proposed to build functional and perfusable vascular networks in 3D tissue-engineered constructs to ensure the long-term [...] Read more.

The development of complex and large 3D vascularized tissue constructs remains the major goal of tissue engineering and regenerative medicine (TERM). To date, several strategies have been proposed to build functional and perfusable vascular networks in 3D tissue-engineered constructs to ensure the long-term cell survival and the functionality of the assembled tissues after implantation. However, none of them have been entirely successful in attaining a fully functional vascular network. Herein, we report an alternative approach to bioengineer 3D vascularized constructs by embedding bioinstructive 3D multilayered microchannels, developed by combining 3D printing with the layer-by-layer (LbL) assembly technology, in photopolymerizable hydrogels. Alginate (ALG) was chosen as the ink to produce customizable 3D sacrificial microstructures owing to its biocompatibility and structural similarity to the extracellular matrices of native tissues. ALG structures were further LbL coated with bioinstructive chitosan and arginine–glycine–aspartic acid-coupled ALG multilayers, embedded in shear-thinning photocrosslinkable xanthan gum hydrogels and exposed to a calcium-chelating solution to form perfusable multilayered microchannels, mimicking the biological barriers, such as the basement membrane, in which the endothelial cells were seeded, denoting an enhanced cell adhesion. The 3D constructs hold great promise for engineering a wide array of large-scale 3D vascularized tissue constructs for modular TERM strategies. Full article

(This article belongs to the Special Issue Biological Biomaterials for Regenerative Medicine)

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25 pages, 12270 KiB

Open AccessEditor’s ChoiceReview

Inhibition of Glycine Re-Uptake: A Potential Approach for Treating Pain by Augmenting Glycine-Mediated Spinal Neurotransmission and Blunting Central Nociceptive Signaling

by Christopher L. Cioffi

Biomolecules 2021, 11(6), 864; https://doi.org/10.3390/biom11060864 - 10 Jun 2021

Cited by 15 | Viewed by 5791

Abstract

Among the myriad of cellular and molecular processes identified as contributing to pathological pain, disinhibition of spinal cord nociceptive signaling to higher cortical centers plays a critical role. Importantly, evidence suggests that impaired glycinergic neurotransmission develops in the dorsal horn of the spinal [...] Read more.

Among the myriad of cellular and molecular processes identified as contributing to pathological pain, disinhibition of spinal cord nociceptive signaling to higher cortical centers plays a critical role. Importantly, evidence suggests that impaired glycinergic neurotransmission develops in the dorsal horn of the spinal cord in inflammatory and neuropathic pain models and is a key maladaptive mechanism causing mechanical hyperalgesia and allodynia. Thus, it has been hypothesized that pharmacological agents capable of augmenting glycinergic tone within the dorsal horn may be able to blunt or block aberrant nociceptor signaling to the brain and serve as a novel class of analgesics for various pathological pain states. Indeed, drugs that enhance dysfunctional glycinergic transmission, and in particular inhibitors of the glycine transporters (GlyT1 and GlyT2), are generating widespread interest as a potential class of novel analgesics. The GlyTs are Na⁺/Cl⁻-dependent transporters of the solute carrier 6 (SLC6) family and it has been proposed that the inhibition of them presents a possible mechanism by which to increase spinal extracellular glycine concentrations and enhance GlyR-mediated inhibitory neurotransmission in the dorsal horn. Various inhibitors of both GlyT1 and GlyT2 have demonstrated broad analgesic efficacy in several preclinical models of acute and chronic pain, providing promise for the approach to deliver a first-in-class non-opioid analgesic with a mechanism of action differentiated from current standard of care. This review will highlight the therapeutic potential of GlyT inhibitors as a novel class of analgesics, present recent advances reported for the field, and discuss the key challenges associated with the development of a GlyT inhibitor into a safe and effective agent to treat pain. Full article

(This article belongs to the Special Issue Glycine Transporters and Receptors as Targets for Analgesics)

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18 pages, 4133 KiB

Open AccessEditor’s ChoiceArticle

Polystyrene Nanoplastics as Carriers of Metals. Interactions of Polystyrene Nanoparticles with Silver Nanoparticles and Silver Nitrate, and Their Effects on Human Intestinal Caco-2 Cells

by Josefa Domenech, Constanza Cortés, Lourdes Vela, Ricard Marcos and Alba Hernández

Biomolecules 2021, 11(6), 859; https://doi.org/10.3390/biom11060859 - 9 Jun 2021

Cited by 41 | Viewed by 6096

Abstract

Environmental plastic wastes are continuously degraded to their micro and nanoforms. Since in the environment they coexist with other pollutants, it has been suggested that they could act as vectors transporting different toxic trace elements, such as metals. To confirm this, we have [...] Read more.

Environmental plastic wastes are continuously degraded to their micro and nanoforms. Since in the environment they coexist with other pollutants, it has been suggested that they could act as vectors transporting different toxic trace elements, such as metals. To confirm this, we have assessed the potential interactions between nanopolystyrene, as a model of nanoplastic debris, and silver compounds (silver nanoparticles and silver nitrate), as models of metal contaminant. Using TEM-EDX methodological approaches, we have been able to demonstrate metal sorption by nanopolystyrene. Furthermore, using Caco-2 cells and confocal microscopy, we have observed the co-localization of nanopolystyrene/nanosilver in different cellular compartments, including the cell nucleus. Although the internalization of these complexes showed no exacerbated cytotoxic effects, compared to the effects of each compound alone, the silver/nanopolystyrene complexes modulate the cell’s uptake of silver and slightly modify some harmful cellular effects of silver, such as the ability to induce genotoxic and oxidative DNA damage. Full article

(This article belongs to the Special Issue How Environmental Plastic Particles and Their Adsorbed Contaminants Interact with Biomolecules?)

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47 pages, 14889 KiB

Open AccessEditor’s ChoiceReview

Exosome-Derived MicroRNAs of Human Milk and Their Effects on Infant Health and Development

by Bodo C. Melnik, Wolfgang Stremmel, Ralf Weiskirchen, Swen Malte John and Gerd Schmitz

Biomolecules 2021, 11(6), 851; https://doi.org/10.3390/biom11060851 - 7 Jun 2021

Cited by 129 | Viewed by 13206

Abstract

Multiple biologically active components of human milk support infant growth, health and development. Milk provides a wide spectrum of mammary epithelial cell-derived extracellular vesicles (MEVs) for the infant. Although the whole spectrum of MEVs appears to be of functional importance for the growing [...] Read more.

Multiple biologically active components of human milk support infant growth, health and development. Milk provides a wide spectrum of mammary epithelial cell-derived extracellular vesicles (MEVs) for the infant. Although the whole spectrum of MEVs appears to be of functional importance for the growing infant, the majority of recent studies report on the MEV subfraction of milk exosomes (MEX) and their miRNA cargo, which are in the focus of this review. MEX and the dominant miRNA-148a play a key role in intestinal maturation, barrier function and suppression of nuclear factor-κB (NF-κB) signaling and may thus be helpful for the prevention and treatment of necrotizing enterocolitis. MEX and their miRNAs reach the systemic circulation and may impact epigenetic programming of various organs including the liver, thymus, brain, pancreatic islets, beige, brown and white adipose tissue as well as bones. Translational evidence indicates that MEX and their miRNAs control the expression of global cellular regulators such as DNA methyltransferase 1—which is important for the up-regulation of developmental genes including insulin, insulin-like growth factor-1, α-synuclein and forkhead box P3—and receptor-interacting protein 140, which is important for the regulation of multiple nuclear receptors. MEX-derived miRNA-148a and miRNA-30b may stimulate the expression of uncoupling protein 1, the key inducer of thermogenesis converting white into beige/brown adipose tissue. MEX have to be considered as signalosomes derived from the maternal lactation genome emitted to promote growth, maturation, immunological and metabolic programming of the offspring. Deeper insights into milk’s molecular biology allow the conclusion that infants are both “breast-fed” and “breast-programmed”. In this regard, MEX miRNA-deficient artificial formula is not an adequate substitute for breastfeeding, the birthright of all mammals. Full article

(This article belongs to the Special Issue Breast Milk-Derived Biomolecules in Human Health)

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13 pages, 2234 KiB

Open AccessEditor’s ChoiceArticle

JMJ Histone Demethylases Balance H3K27me3 and H3K4me3 Levels at the HSP21 Locus during Heat Acclimation in Arabidopsis

by Nobutoshi Yamaguchi and Toshiro Ito

Biomolecules 2021, 11(6), 852; https://doi.org/10.3390/biom11060852 - 7 Jun 2021

Cited by 23 | Viewed by 4909

Abstract

Exposure to moderately high temperature enables plants to acquire thermotolerance to high temperatures that might otherwise be lethal. In Arabidopsis thaliana, histone H3 lysine 27 trimethylation (H3K27me3) at the heat shock protein 17.6C (HSP17.6C) and HSP22 loci is removed by [...] Read more.

Exposure to moderately high temperature enables plants to acquire thermotolerance to high temperatures that might otherwise be lethal. In Arabidopsis thaliana, histone H3 lysine 27 trimethylation (H3K27me3) at the heat shock protein 17.6C (HSP17.6C) and HSP22 loci is removed by Jumonji C domain-containing protein (JMJ) histone demethylases, thus allowing the plant to ‘remember’ the heat experience. Other heat memory genes, such as HSP21, are downregulated in acclimatized jmj quadruple mutants compared to the wild type, but how those genes are regulated remains uncharacterized. Here, we show that histone H3 lysine 4 trimethylation (H3K4me3) at HSP21 was maintained at high levels for at least three days in response to heat. This heat-dependent H3K4me3 accumulation was compromised in the acclimatized jmj quadruple mutant as compared to the acclimatized wild type. JMJ30 directly bound to the HSP21 locus in response to heat and coordinated H3K27me3 and H3K4me3 levels under standard and fluctuating conditions. Our results suggest that JMJs mediate the balance between H3K27me3 and H3K4me3 at the HSP21 locus through proper maintenance of H3K27me3 removal during heat acclimation. Full article

(This article belongs to the Special Issue Recent Advances and Applications of Biostimulants for Plant Growth Promotion and Environmental Stress Adaptation)

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12 pages, 478 KiB

Open AccessEditor’s ChoiceArticle

Exploring the Connection between Porphyromonas gingivalis and Neurodegenerative Diseases: A Pilot Quantitative Study on the Bacterium Abundance in Oral Cavity and the Amount of Antibodies in Serum

by Raffaella Franciotti, Pamela Pignatelli, Claudia Carrarini, Federica Maria Romei, Martina Mastrippolito, Antonella Gentile, Rosa Mancinelli, Stefania Fulle, Adriano Piattelli, Marco Onofrj and Maria Cristina Curia

Biomolecules 2021, 11(6), 845; https://doi.org/10.3390/biom11060845 - 6 Jun 2021

Cited by 24 | Viewed by 5776

Abstract

Recent studies support the hypothesis that microbes can seed some Alzheimer’s disease (AD) cases, leading to inflammation and overproduction of amyloid peptides. Porphyromonas gingivalis (Pg) is a keystone pathogen of chronic periodontitis and has been identified as risk factor for the development and [...] Read more.

Recent studies support the hypothesis that microbes can seed some Alzheimer’s disease (AD) cases, leading to inflammation and overproduction of amyloid peptides. Porphyromonas gingivalis (Pg) is a keystone pathogen of chronic periodontitis and has been identified as risk factor for the development and progression of AD. The present preliminary study aimed to quantify Pg abundance in neurodegenerative disease (ND) patients compared with neurologic patients without neurodegenerative disorders (no-ND) and healthy controls (HC) to determine possible association between Pg abundance and neurodegenerative process. Pg was quantified on DNA extracted from the oral samples of 49 patients and 29 HC by quantitative polymerase chain reaction (qPCR). Anti-Pg antibodies were also detected on patient serum samples by enzyme-linked immunosorbent assays (ELISA). The Pg abundance in the oral cavity was significantly different among groups (p = 0.004). It was higher in ND than no-ND (p = 0.010) and HC (p = 0.008). The Pg abundance was correlated with the antibodies (p = 0.001) with different slopes between ND and no-ND (p = 0.037). Pg abundance was not correlated with oral indices and comorbidities. These results extend our understanding of the association between oral pathogens and AD to other neurodegenerative processes, confirming the hypothesis that oral pathogens can induce an antibody systemic response, influencing the progression of the disease. Full article

(This article belongs to the Collection Natural and Synthetic Compounds in Neurodegenerative Disorders)

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13 pages, 3688 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Glycine Receptors in Spinal Nociceptive Control—An Update

by Hanns Ulrich Zeilhofer, Karolina Werynska, Jacinthe Gingras and Gonzalo E. Yévenes

Biomolecules 2021, 11(6), 846; https://doi.org/10.3390/biom11060846 - 6 Jun 2021

Cited by 32 | Viewed by 6174

Abstract

Diminished inhibitory control of spinal nociception is one of the major culprits of chronic pain states. Restoring proper synaptic inhibition is a well-established rational therapeutic approach explored by several pharmaceutical companies. A particular challenge arises from the need for site-specific intervention to avoid [...] Read more.

Diminished inhibitory control of spinal nociception is one of the major culprits of chronic pain states. Restoring proper synaptic inhibition is a well-established rational therapeutic approach explored by several pharmaceutical companies. A particular challenge arises from the need for site-specific intervention to avoid deleterious side effects such as sedation, addiction, or impaired motor control, which would arise from wide-range facilitation of inhibition. Specific targeting of glycinergic inhibition, which dominates in the spinal cord and parts of the hindbrain, may help reduce these side effects. Selective targeting of the α3 subtype of glycine receptors (GlyRs), which is highly enriched in the superficial layers of the spinal dorsal horn, a key site of nociceptive processing, may help to further narrow down pharmacological intervention on the nociceptive system and increase tolerability. This review provides an update on the physiological properties and functions of α3 subtype GlyRs and on the present state of related drug discovery programs. Full article

(This article belongs to the Special Issue Glycine Transporters and Receptors as Targets for Analgesics)

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23 pages, 3522 KiB

Open AccessEditor’s ChoiceReview

Folding and Stability of Ankyrin Repeats Control Biological Protein Function

by Amit Kumar and Jochen Balbach

Biomolecules 2021, 11(6), 840; https://doi.org/10.3390/biom11060840 - 5 Jun 2021

Cited by 29 | Viewed by 7356

Abstract

Ankyrin repeat proteins are found in all three kingdoms of life. Fundamentally, these proteins are involved in protein-protein interaction in order to activate or suppress biological processes. The basic architecture of these proteins comprises repeating modules forming elongated structures. Due to the lack [...] Read more.

Ankyrin repeat proteins are found in all three kingdoms of life. Fundamentally, these proteins are involved in protein-protein interaction in order to activate or suppress biological processes. The basic architecture of these proteins comprises repeating modules forming elongated structures. Due to the lack of long-range interactions, a graded stability among the repeats is the generic properties of this protein family determining both protein folding and biological function. Protein folding intermediates were frequently found to be key for the biological functions of repeat proteins. In this review, we discuss most recent findings addressing this close relation for ankyrin repeat proteins including DARPins, Notch receptor ankyrin repeat domain, IκBα inhibitor of NFκB, and CDK inhibitor p19^INK4d. The role of local folding and unfolding and gradual stability of individual repeats will be discussed during protein folding, protein-protein interactions, and post-translational modifications. The conformational changes of these repeats function as molecular switches for biological regulation, a versatile property for modern drug discovery. Full article

(This article belongs to the Special Issue Protein Folding Stability and Dynamics: Commemorative Issue in Honor of Professor Sir Christopher Dobson (1949–2019))

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17 pages, 360 KiB

Open AccessEditor’s ChoiceReview

MicroRNA as a Novel Biomarker in the Diagnosis of Head and Neck Cancer

by Jacek Kabzinski, Monika Maczynska and Ireneusz Majsterek

Biomolecules 2021, 11(6), 844; https://doi.org/10.3390/biom11060844 - 5 Jun 2021

Cited by 41 | Viewed by 5969

Abstract

Head and neck squamous cell carcinoma is the sixth most common cancer worldwide, with 890,000 new cases and 450,000 deaths in 2018, and although the survival statistics for some patient groups are improving, there is still an urgent need to find a fast [...] Read more.

Head and neck squamous cell carcinoma is the sixth most common cancer worldwide, with 890,000 new cases and 450,000 deaths in 2018, and although the survival statistics for some patient groups are improving, there is still an urgent need to find a fast and reliable biomarker that allows early diagnosis. This niche can be filled by microRNA, small single-stranded non-coding RNA molecules, which are expressed in response to specific events in the body. This article presents the potential use of microRNAs in the diagnosis of HNSCC, compares the advances in this field to other diseases, especially other cancers, and discusses the detailed use of miRNA as a biomarker in profiling and predicting the treatment outcome with radiotherapy and immunotherapy. Potential problems and difficulties related to the development of this promising technology, and areas on which future research should be focused in order to overcome these difficulties, were also indicated. Full article

(This article belongs to the Special Issue Genetics and Molecular Biology of Head and Neck Cancer)

9 pages, 6289 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

SARS-CoV-2 and Skin: The Pathologist’s Point of View

by Gerardo Cazzato, Giulia Mazzia, Antonietta Cimmino, Anna Colagrande, Sara Sablone, Teresa Lettini, Roberta Rossi, Nadia Santarella, Rossella Elia, Eleonora Nacchiero, Michele Maruccia, Andrea Marzullo, Eugenio Maiorano, Giuseppe Giudice, Giuseppe Ingravallo and Leonardo Resta

Biomolecules 2021, 11(6), 838; https://doi.org/10.3390/biom11060838 - 4 Jun 2021

Cited by 14 | Viewed by 3444

Abstract

The SARS-CoV-2 pandemic has dramatically changed our lives and habits. In just a few months, the most advanced and efficient health systems in the world have been overwhelmed by an infectious disease that has caused 3.26 million deaths and more than 156 million [...] Read more.

The SARS-CoV-2 pandemic has dramatically changed our lives and habits. In just a few months, the most advanced and efficient health systems in the world have been overwhelmed by an infectious disease that has caused 3.26 million deaths and more than 156 million cases worldwide. Although the lung is the most frequently affected organ, the skin has also resulted in being a target body district, so much so as to suggest it may be a real “sentinel” of COVID-19 disease. Here we present 17 cases of skin manifestations studied and analyzed in recent months in our Department; immunohistochemical investigations were carried out on samples for the S1 spike-protein of SARS-CoV-2, as well as electron microscopy investigations showing evidence of virions within the constituent cells of the eccrine sweat glands and the endothelium of small blood vessels. Finally, we conduct a brief review of the COVID-related skin manifestations, confirmed by immunohistochemistry and/or electron microscopy, described in the literature. Full article

(This article belongs to the Special Issue State-of-the-Art on COVID-19 Disease in Italy- The Pathologist’s Experience)

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18 pages, 5209 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

Parallel and Sequential Pathways of Molecular Recognition of a Tandem-Repeat Protein and Its Intrinsically Disordered Binding Partner

by Ben M. Smith, Pamela J. E. Rowling, Christopher M. Dobson and Laura S. Itzhaki

Biomolecules 2021, 11(6), 827; https://doi.org/10.3390/biom11060827 - 1 Jun 2021

Cited by 6 | Viewed by 4120

Abstract

The Wnt signalling pathway plays an important role in cell proliferation, differentiation, and fate decisions in embryonic development and the maintenance of adult tissues. The twelve armadillo (ARM) repeat-containing protein β-catenin acts as the signal transducer in this pathway. Here, we investigated the [...] Read more.

The Wnt signalling pathway plays an important role in cell proliferation, differentiation, and fate decisions in embryonic development and the maintenance of adult tissues. The twelve armadillo (ARM) repeat-containing protein β-catenin acts as the signal transducer in this pathway. Here, we investigated the interaction between β-catenin and the intrinsically disordered transcription factor TCF7L2, comprising a very long nanomolar-affinity interface of approximately 4800 Å² that spans ten of the twelve ARM repeats of β-catenin. First, a fluorescence reporter system for the interaction was engineered and used to determine the kinetic rate constants for the association and dissociation. The association kinetics of TCF7L2 and β-catenin were monophasic and rapid (7.3 ± 0.1 × 10⁷ M⁻¹·s⁻¹), whereas dissociation was biphasic and slow (5.7 ± 0.4 × 10⁻⁴ s⁻¹, 15.2 ± 2.8 × 10⁻⁴ s⁻¹). This reporter system was then combined with site-directed mutagenesis to investigate the striking variability in the conformation adopted by TCF7L2 in the three different crystal structures of the TCF7L2–β-catenin complex. We found that the mutation had very little effect on the association kinetics, indicating that most interactions form after the rate-limiting barrier for association. Mutations of the N- and C-terminal subdomains of TCF7L2 that adopt relatively fixed conformations in the crystal structures had large effects on the dissociation kinetics, whereas the mutation of the labile sub-domain connecting them had negligible effect. These results point to a two-site avidity mechanism of binding with the linker region forming a “fuzzy” complex involving transient contacts that are not site-specific. Strikingly, the two mutations in the N-terminal subdomain that had the largest effects on the dissociation kinetics showed two additional phases, indicating partial flux through an alternative dissociation pathway that is inaccessible to the wild type. The results presented here provide insights into the kinetics of the molecular recognition of a long intrinsically disordered region with an elongated repeat-protein surface, a process found to involve parallel routes with sequential steps in each. Full article

(This article belongs to the Special Issue Protein Folding Stability and Dynamics: Commemorative Issue in Honor of Professor Sir Christopher Dobson (1949–2019))

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18 pages, 693 KiB

Open AccessEditor’s ChoiceReview

Sustainable Agriculture Systems in Vegetable Production Using Chitin and Chitosan as Plant Biostimulants

by Mohamad Hesam Shahrajabian, Christina Chaski, Nikolaos Polyzos, Nikolaos Tzortzakis and Spyridon A. Petropoulos

Biomolecules 2021, 11(6), 819; https://doi.org/10.3390/biom11060819 - 31 May 2021

Cited by 148 | Viewed by 13306

Abstract

Chitin and chitosan are natural compounds that are biodegradable and nontoxic and have gained noticeable attention due to their effective contribution to increased yield and agro-environmental sustainability. Several effects have been reported for chitosan application in plants. Particularly, it can be used in [...] Read more.

Chitin and chitosan are natural compounds that are biodegradable and nontoxic and have gained noticeable attention due to their effective contribution to increased yield and agro-environmental sustainability. Several effects have been reported for chitosan application in plants. Particularly, it can be used in plant defense systems against biological and environmental stress conditions and as a plant growth promoter—it can increase stomatal conductance and reduce transpiration or be applied as a coating material in seeds. Moreover, it can be effective in promoting chitinolytic microorganisms and prolonging storage life through post-harvest treatments, or benefit nutrient delivery to plants since it may prevent leaching and improve slow release of nutrients in fertilizers. Finally, it can remediate polluted soils through the removal of cationic and anionic heavy metals and the improvement of soil properties. On the other hand, chitin also has many beneficial effects such as plant growth promotion, improved plant nutrition and ability to modulate and improve plants’ resistance to abiotic and biotic stressors. The present review presents a literature overview regarding the effects of chitin, chitosan and derivatives on horticultural crops, highlighting their important role in modern sustainable crop production; the main limitations as well as the future prospects of applications of this particular biostimulant category are also presented. Full article

(This article belongs to the Special Issue Recent Advances and Applications of Biostimulants for Plant Growth Promotion and Environmental Stress Adaptation)

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22 pages, 871 KiB

Open AccessEditor’s ChoiceReview

Effects of Anthocyanins on Vascular Health

by Ioana Mozos, Corina Flangea, Daliborca C. Vlad, Cristina Gug, Costin Mozos, Dana Stoian, Constantin T. Luca, Jarosław O. Horbańczuk, Olaf K. Horbańczuk and Atanas G. Atanasov

Biomolecules 2021, 11(6), 811; https://doi.org/10.3390/biom11060811 - 30 May 2021

Cited by 74 | Viewed by 8439

Abstract

Cardiovascular disorders are leading mortality causes worldwide, often with a latent evolution. Vascular health depends on endothelial function, arterial stiffness, and the presence of atherosclerotic plaques. Preventive medicine deserves special attention, focusing on modifiable cardiovascular risk factors, including diet. A diet rich in [...] Read more.

Cardiovascular disorders are leading mortality causes worldwide, often with a latent evolution. Vascular health depends on endothelial function, arterial stiffness, and the presence of atherosclerotic plaques. Preventive medicine deserves special attention, focusing on modifiable cardiovascular risk factors, including diet. A diet rich in fruits and vegetables has well-known health benefits, especially due to its polyphenolic components. Anthocyanins, water-soluble flavonoid species, responsible for the red-blue color in plants and commonly found in berries, exert favorable effects on the endothelial function, oxidative stress, inhibit COX-1, and COX-2 enzymes, exert antiatherogenic, antihypertensive, antiglycation, antithrombotic, and anti-inflammatory activity, ameliorate dyslipidemia and arterial stiffness. The present review aims to give a current overview of the mechanisms involved in the vascular protective effect of anthocyanins from the human diet, considering epidemiological data, in vitro and in vivo preclinical research, clinical observational, retrospective, intervention and randomized studies, dietary and biomarker studies, and discussing preventive benefits of anthocyanins and future research directions. Full article

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22 pages, 921 KiB

Open AccessFeature PaperEditor’s ChoiceReview

The Role of the Key Effector of Necroptotic Cell Death, MLKL, in Mouse Models of Disease

by Emma C. Tovey Crutchfield, Sarah E. Garnish and Joanne M. Hildebrand

Biomolecules 2021, 11(6), 803; https://doi.org/10.3390/biom11060803 - 28 May 2021

Cited by 21 | Viewed by 5110

Abstract

Necroptosis is an inflammatory form of lytic programmed cell death that is thought to have evolved to defend against pathogens. Genetic deletion of the terminal effector protein—MLKL—shows no overt phenotype in the C57BL/6 mouse strain under conventional laboratory housing conditions. Small molecules that [...] Read more.

Necroptosis is an inflammatory form of lytic programmed cell death that is thought to have evolved to defend against pathogens. Genetic deletion of the terminal effector protein—MLKL—shows no overt phenotype in the C57BL/6 mouse strain under conventional laboratory housing conditions. Small molecules that inhibit necroptosis by targeting the kinase activity of RIPK1, one of the main upstream conduits to MLKL activation, have shown promise in several murine models of non-infectious disease and in phase II human clinical trials. This has triggered in excess of one billion dollars (USD) in investment into the emerging class of necroptosis blocking drugs, and the potential utility of targeting the terminal effector is being closely scrutinised. Here we review murine models of disease, both genetic deletion and mutation, that investigate the role of MLKL. We summarize a series of examples from several broad disease categories including ischemia reperfusion injury, sterile inflammation, pathogen infection and hematological stress. Elucidating MLKL’s contribution to mouse models of disease is an important first step to identify human indications that stand to benefit most from MLKL-targeted drug therapies. Full article

(This article belongs to the Special Issue Cell Death in Cancer and Inflammation: From Pathogenesis to Treatment)

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16 pages, 2936 KiB

Open AccessEditor’s ChoiceArticle

Lower Gene Expression of Angiotensin Converting Enzyme 2 Receptor in Lung Tissues of Smokers with COVID-19 Pneumonia

by Francesca Lunardi, Francesco Fortarezza, Luca Vedovelli, Federica Pezzuto, Annalisa Boscolo, Marco Rossato, Roberto Vettor, Anna Maria Cattelan, Claudia Del Vecchio, Andrea Crisanti, Paolo Navalesi, Dario Gregori and Fiorella Calabrese

Biomolecules 2021, 11(6), 796; https://doi.org/10.3390/biom11060796 - 26 May 2021

Cited by 2 | Viewed by 3313

Abstract

Angiotensin-converting enzyme 2 (ACE-2) is the main cell entry receptor for severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2), thus playing a critical role in causing Coronavirus disease 2019 (COVID-19). The role of smoking habit in the susceptibility to infection is still controversial. In this study [...] Read more.

Angiotensin-converting enzyme 2 (ACE-2) is the main cell entry receptor for severe acute respiratory syndrome-Coronavirus-2 (SARS-CoV-2), thus playing a critical role in causing Coronavirus disease 2019 (COVID-19). The role of smoking habit in the susceptibility to infection is still controversial. In this study we correlated lung ACE-2 gene expression with several clinical/pathological data to explore susceptibility to infection. This is a retrospective observational study on 29 consecutive COVID-19 autopsies. SARS-CoV-2 genome and ACE-2 mRNA expression were evaluated by real-time polymerase chain reaction in lung tissue samples and correlated with several data with focus on smoking habit. Smoking was less frequent in high than low ACE-2 expressors (p = 0.014). A Bayesian regression also including age, gender, hypertension, and virus quantity confirmed that smoking was the most probable risk factor associated with low ACE-2 expression in the model. A direct relation was found between viral quantity and ACE-2 expression (p = 0.028). Finally, high ACE-2 expressors more frequently showed a prevalent pattern of vascular injury than low expressors (p = 0.049). In conclusion, ACE-2 levels were decreased in the lung tissue of smokers with severe COVID-19 pneumonia. These results point out complex biological interactions between SARS-CoV-2 and ACE-2 particularly concerning the aspect of smoking habit and need larger prospective case series and translational studies. Full article

(This article belongs to the Special Issue State-of-the-Art on COVID-19 Disease in Italy- The Pathologist’s Experience)

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33 pages, 2611 KiB

Open AccessEditor’s ChoiceReview

Oximes: Novel Therapeutics with Anticancer and Anti-Inflammatory Potential

by Igor A. Schepetkin, Mark B. Plotnikov, Andrei I. Khlebnikov, Tatiana M. Plotnikova and Mark T. Quinn

Biomolecules 2021, 11(6), 777; https://doi.org/10.3390/biom11060777 - 22 May 2021

Cited by 57 | Viewed by 7772

Abstract

Oximes have been studied for decades because of their significant roles as acetylcholinesterase reactivators. Over the last twenty years, a large number of oximes have been reported with useful pharmaceutical properties, including compounds with antibacterial, anticancer, anti-arthritis, and anti-stroke activities. Many oximes are [...] Read more.

Oximes have been studied for decades because of their significant roles as acetylcholinesterase reactivators. Over the last twenty years, a large number of oximes have been reported with useful pharmaceutical properties, including compounds with antibacterial, anticancer, anti-arthritis, and anti-stroke activities. Many oximes are kinase inhibitors and have been shown to inhibit over 40 different kinases, including AMP-activated protein kinase (AMPK), phosphatidylinositol 3-kinase (PI3K), cyclin-dependent kinase (CDK), serine/threonine kinases glycogen synthase kinase 3 α/β (GSK-3α/β), Aurora A, B-Raf, Chk1, death-associated protein-kinase-related 2 (DRAK2), phosphorylase kinase (PhK), serum and glucocorticoid-regulated kinase (SGK), Janus tyrosine kinase (JAK), and multiple receptor and non-receptor tyrosine kinases. Some oximes are inhibitors of lipoxygenase 5, human neutrophil elastase, and proteinase 3. The oxime group contains two H-bond acceptors (nitrogen and oxygen atoms) and one H-bond donor (OH group), versus only one H-bond acceptor present in carbonyl groups. This feature, together with the high polarity of oxime groups, may lead to a significantly different mode of interaction with receptor binding sites compared to corresponding carbonyl compounds, despite small changes in the total size and shape of the compound. In addition, oximes can generate nitric oxide. This review is focused on oximes as kinase inhibitors with anticancer and anti-inflammatory activities. Oximes with non-kinase targets or mechanisms of anti-inflammatory activity are also discussed. Full article

(This article belongs to the Collection Feature Papers in Biochemistry)

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22 pages, 2069 KiB

Open AccessEditor’s ChoiceReview

Mechanisms That Activate 26S Proteasomes and Enhance Protein Degradation

by Alfred L. Goldberg, Hyoung Tae Kim, Donghoon Lee and Galen Andrew Collins

Biomolecules 2021, 11(6), 779; https://doi.org/10.3390/biom11060779 - 22 May 2021

Cited by 30 | Viewed by 8420

Abstract

Although ubiquitination is widely assumed to be the only regulated step in the ubiquitin–proteasome pathway, recent studies have demonstrated several important mechanisms that regulate the activities of the 26S proteasome. Most proteasomes in cells are inactive but, upon binding a ubiquitinated substrate, become [...] Read more.

Although ubiquitination is widely assumed to be the only regulated step in the ubiquitin–proteasome pathway, recent studies have demonstrated several important mechanisms that regulate the activities of the 26S proteasome. Most proteasomes in cells are inactive but, upon binding a ubiquitinated substrate, become activated by a two-step mechanism requiring an association of the ubiquitin chain with Usp14 and then a loosely folded protein domain with the ATPases. The initial activation step is signaled by Usp14’s UBL domain, and many UBL-domain-containing proteins (e.g., Rad23, Parkin) also activate the proteasome. ZFAND5 is a distinct type of activator that binds ubiquitin conjugates and the proteasome and stimulates proteolysis during muscle atrophy. The proteasome’s activities are also regulated through subunit phosphorylation. Agents that raise cAMP and activate PKA stimulate within minutes Rpn6 phosphorylation and enhance the selective degradation of short-lived proteins. Likewise, hormones, fasting, and exercise, which raise cAMP, activate proteasomes and proteolysis in target tissues. Agents that raise cGMP and activate PKG also stimulate 26S activities but modify different subunit(s) and stimulate also the degradation of long-lived cell proteins. Both kinases enhance the selective degradation of aggregation-prone proteins that cause neurodegenerative diseases. These new mechanisms regulating proteolysis thus have clear physiological importance and therapeutic potential. Full article

(This article belongs to the Special Issue Regulating Proteasome Activity)

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21 pages, 1770 KiB

Open AccessEditor’s ChoiceReview

DEER Analysis of GPCR Conformational Heterogeneity

by Matthias Elgeti and Wayne L. Hubbell

Biomolecules 2021, 11(6), 778; https://doi.org/10.3390/biom11060778 - 22 May 2021

Cited by 30 | Viewed by 6244

Abstract

G protein-coupled receptors (GPCRs) represent a large class of transmembrane helical proteins which are involved in numerous physiological signaling pathways and therefore represent crucial pharmacological targets. GPCR function and the action of therapeutic molecules are defined by only a few parameters, including receptor [...] Read more.

G protein-coupled receptors (GPCRs) represent a large class of transmembrane helical proteins which are involved in numerous physiological signaling pathways and therefore represent crucial pharmacological targets. GPCR function and the action of therapeutic molecules are defined by only a few parameters, including receptor basal activity, ligand affinity, intrinsic efficacy and signal bias. These parameters are encoded in characteristic receptor conformations existing in equilibrium and their populations, which are thus of paramount interest for the understanding of receptor (mal-)functions and rational design of improved therapeutics. To this end, the combination of site-directed spin labeling and EPR spectroscopy, in particular double electron–electron resonance (DEER), is exceedingly valuable as it has access to sub-Angstrom spatial resolution and provides a detailed picture of the number and populations of conformations in equilibrium. This review gives an overview of existing DEER studies on GPCRs with a focus on the delineation of structure/function frameworks, highlighting recent developments in data analysis and visualization. We introduce “conformational efficacy” as a parameter to describe ligand-specific shifts in the conformational equilibrium, taking into account the loose coupling between receptor segments observed for different GPCRs using DEER. Full article

(This article belongs to the Special Issue GPCRs: Structure, Biology and Potential Applications)

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12 pages, 493 KiB

Open AccessEditor’s ChoiceReview

Can Cannabidiol Affect the Efficacy of Chemotherapy and Epigenetic Treatments in Cancer?

by Courtney Griffiths, James Aikins, David Warshal and Olga Ostrovsky

Biomolecules 2021, 11(5), 766; https://doi.org/10.3390/biom11050766 - 20 May 2021

Cited by 21 | Viewed by 6031

Abstract

The success of cannabinoids with chronic neuropathic pain and anxiety has been demonstrated in a multitude of studies. With the high availability of a non-intoxicating compound, cannabidiol (CBD), an over-the-counter medication, has generated heightened interest in its use in the field of oncology. [...] Read more.

The success of cannabinoids with chronic neuropathic pain and anxiety has been demonstrated in a multitude of studies. With the high availability of a non-intoxicating compound, cannabidiol (CBD), an over-the-counter medication, has generated heightened interest in its use in the field of oncology. This review focuses on the widespread therapeutic potential of CBD with regard to enhanced wound healing, lowered toxicity profiles of chemotherapeutics, and augmented antitumorigenic effects. The current literature is sparse with regard to determining the clinically relevant concentrations of CBD given the biphasic nature of the compound’s response. Therefore, there is an imminent need for further dose-finding studies in order to determine the optimal dose of CBD for both intermittent and regular users. We address the potential influence of regular or occasional CBD usage on therapeutic outcomes in ovarian cancer patients. Additionally, as the development of chemoresistance in ovarian cancer results in treatment failure, the potential for CBD to augment the efficacy of conventional chemotherapeutic and epigenetic drugs is a topic of significant importance. Our review is focused on the widespread therapeutic potential of CBD and whether or not a synergistic role exists in combination with epigenetic and classic chemotherapy medications. Full article

(This article belongs to the Special Issue Novel Indications of Epigenetic Therapy in Cancer)

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18 pages, 3807 KiB

Open AccessEditor’s ChoiceArticle

Proton Detected Solid-State NMR of Membrane Proteins at 28 Tesla (1.2 GHz) and 100 kHz Magic-Angle Spinning

by Evgeny Nimerovsky, Kumar Tekwani Movellan, Xizhou Cecily Zhang, Marcel C. Forster, Eszter Najbauer, Kai Xue, Rıza Dervişoǧlu, Karin Giller, Christian Griesinger, Stefan Becker and Loren B. Andreas

Biomolecules 2021, 11(5), 752; https://doi.org/10.3390/biom11050752 - 18 May 2021

Cited by 50 | Viewed by 6254

Abstract

The available magnetic field strength for high resolution NMR in persistent superconducting magnets has recently improved from 23.5 to 28 Tesla, increasing the proton resonance frequency from 1 to 1.2 GHz. For magic-angle spinning (MAS) NMR, this is expected to improve resolution, provided [...] Read more.

The available magnetic field strength for high resolution NMR in persistent superconducting magnets has recently improved from 23.5 to 28 Tesla, increasing the proton resonance frequency from 1 to 1.2 GHz. For magic-angle spinning (MAS) NMR, this is expected to improve resolution, provided the sample preparation results in homogeneous broadening. We compare two-dimensional (2D) proton detected MAS NMR spectra of four membrane proteins at 950 and 1200 MHz. We find a consistent improvement in resolution that scales superlinearly with the increase in magnetic field for three of the four examples. In 3D and 4D spectra, which are now routinely acquired, this improvement indicates the ability to resolve at least 2 and 2.5 times as many signals, respectively. Full article

(This article belongs to the Special Issue Advances in Membrane Proteins 2021)

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10 pages, 999 KiB

Open AccessEditor’s ChoiceArticle

Plasma Extracellular Vesicle α-Synuclein Level in Patients with Parkinson’s Disease

by Chen-Chih Chung, Lung Chan, Jia-Hung Chen, Yi-Chieh Hung and Chien-Tai Hong

Biomolecules 2021, 11(5), 744; https://doi.org/10.3390/biom11050744 - 17 May 2021

Cited by 22 | Viewed by 3920

Abstract

Background: The most established pathognomonic protein of Parkinson’s disease (PD), α-synuclein, is extensively investigated for disease diagnosis and prognosis; however, investigations into whether the free form of α-synuclein in the blood functions as a PD biomarker have not been fruitful. Extracellular vesicles (EVs) [...] Read more.

Background: The most established pathognomonic protein of Parkinson’s disease (PD), α-synuclein, is extensively investigated for disease diagnosis and prognosis; however, investigations into whether the free form of α-synuclein in the blood functions as a PD biomarker have not been fruitful. Extracellular vesicles (EVs) secreted from cells and present in blood transport molecules are novel platforms for biomarker identification. In blood EVs, α-synuclein originates predominantly from the brain without the interference of the blood–brain barrier. The present study investigated the role of plasma EV-borne α-synuclein as a biomarker of PD. Methods: Patients with mild to moderate stages of PD (n = 116) and individuals without PD (n = 46) were recruited to serve as the PD study group and the control group, respectively. Plasma EVs were isolated, and immunomagnetic reduction–based immunoassay was used to assess EV α-synuclein levels. Conventional statistical analysis was performed using SPSS 25.0, and p < 0.05 was considered significant. Results: Compared with controls, we observed significantly lower plasma EV α-synuclein levels in the patients with PD (PD: 56.0 ± 3.7 fg/mL vs. control: 74.5 ± 4.3 fg/mL, p = 0.009), and the significance remained after adjustment for age and sex. Plasma EV α-synuclein levels in the patients with PD did not correlate with age, disease duration, Part I and II scores of the Unified Parkinson’s Disease Rating Scale (UPDRS), or the Mini-Mental State Examination scores. However, such levels were significantly correlated with UPDRS Part III score, which assesses motor dysfunction. Furthermore, the severity of akinetic-rigidity symptoms, but not tremor, was inversely associated with plasma EV α-synuclein level. Conclusion: Plasma EV α-synuclein was significantly different between the control and PD group and was associated with akinetic-rigidity symptom severity in patients with PD. This study corroborates the possible diagnostic and subtyping roles of plasma EV α-synuclein in patients with PD, and it further provides a basis for this protein’s clinical relevance and feasibility as a PD biomarker. Full article

(This article belongs to the Special Issue Recent Advances in α-Synuclein Neurobiology in Health and Disease)

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20 pages, 4523 KiB

Open AccessEditor’s ChoiceArticle

Beneficial Modulation of Lipid Mediator Biosynthesis in Innate Immune Cells by Antirheumatic Tripterygium wilfordii Glycosides

by Kehong Zhang, Simona Pace, Paul M. Jordan, Lukas K. Peltner, Alexander Weber, Dagmar Fischer, Robert K. Hofstetter, Xinchun Chen and Oliver Werz

Biomolecules 2021, 11(5), 746; https://doi.org/10.3390/biom11050746 - 17 May 2021

Cited by 12 | Viewed by 3814

Abstract

Tripterygium wilfordii glycosides (TWG) is a traditional Chinese medicine with effectiveness against rheumatoid arthritis (RA), supported by numerous clinical trials. Lipid mediators (LM) are biomolecules produced from polyunsaturated fatty acids mainly by cyclooxygenases (COX) and lipoxygenases (LOX) in complex networks which regulate inflammation [...] Read more.

Tripterygium wilfordii glycosides (TWG) is a traditional Chinese medicine with effectiveness against rheumatoid arthritis (RA), supported by numerous clinical trials. Lipid mediators (LM) are biomolecules produced from polyunsaturated fatty acids mainly by cyclooxygenases (COX) and lipoxygenases (LOX) in complex networks which regulate inflammation and immune responses and are strongly linked to RA. The mechanism by which TWG affects LM networks in RA treatment remains elusive. Employing LM metabololipidomics using ultra-performance liquid chromatography-tandem mass spectrometry revealed striking modulation of LM pathways by TWG in human monocyte-derived macrophage (MDM) phenotypes. In inflammatory M1-MDM, TWG (30 µg/mL) potently suppressed agonist-induced formation of 5-LOX products which was confirmed in human PMNL and traced back to direct inhibition of 5-LOX (IC₅₀ = 2.9 µg/mL). TWG also efficiently blocked thromboxane formation in M1-MDM without inhibiting other prostanoids and COX enzymes. Importantly, in anti-inflammatory M2-MDM, TWG (30 µg/mL) induced pronounced formation of specialized pro-resolving mediators (SPM) and related 12/15-LOX-derived SPM precursors, without COX and 5-LOX activation. During MDM polarization, TWG (1 µg/mL) decreased the capacity to generate pro-inflammatory 5-LOX and COX products, cytokines and markers for M1 phenotypes. Together, suppression of pro-inflammatory LM but SPM induction may contribute to the antirheumatic properties of TWG. Full article

(This article belongs to the Collection Bioactive Lipids in Inflammation, Diabetes and Cancer)

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22 pages, 5131 KiB

Open AccessEditor’s ChoiceReview

A Bittersweet Computational Journey among Glycosaminoglycans

by Giulia Paiardi, Maria Milanesi, Rebecca C. Wade, Pasqualina D’Ursi and Marco Rusnati

Biomolecules 2021, 11(5), 739; https://doi.org/10.3390/biom11050739 - 15 May 2021

Cited by 14 | Viewed by 4930

Abstract

Glycosaminoglycans (GAGs) are linear polysaccharides. In proteoglycans (PGs), they are attached to a core protein. GAGs and PGs can be found as free molecules, associated with the extracellular matrix or expressed on the cell membrane. They play a role in the regulation of [...] Read more.

Glycosaminoglycans (GAGs) are linear polysaccharides. In proteoglycans (PGs), they are attached to a core protein. GAGs and PGs can be found as free molecules, associated with the extracellular matrix or expressed on the cell membrane. They play a role in the regulation of a wide array of physiological and pathological processes by binding to different proteins, thus modulating their structure and function, and their concentration and availability in the microenvironment. Unfortunately, the enormous structural diversity of GAGs/PGs has hampered the development of dedicated analytical technologies and experimental models. Similarly, computational approaches (in particular, molecular modeling, docking and dynamics simulations) have not been fully exploited in glycobiology, despite their potential to demystify the complexity of GAGs/PGs at a structural and functional level. Here, we review the state-of-the art of computational approaches to studying GAGs/PGs with the aim of pointing out the “bitter” and “sweet” aspects of this field of research. Furthermore, we attempt to bridge the gap between bioinformatics and glycobiology, which have so far been kept apart by conceptual and technical differences. For this purpose, we provide computational scientists and glycobiologists with the fundamentals of these two fields of research, with the aim of creating opportunities for their combined exploitation, and thereby contributing to a substantial improvement in scientific knowledge. Full article

(This article belongs to the Special Issue Structural and Functional Approach to the Glycan Diversity)

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27 pages, 4242 KiB

Open AccessEditor’s ChoiceReview

Phototheranostics Using Erythrocyte-Based Particles

by Taylor Hanley, Raviraj Vankayala, Chi-Hua Lee, Jack C. Tang, Joshua M. Burns and Bahman Anvari

Biomolecules 2021, 11(5), 729; https://doi.org/10.3390/biom11050729 - 13 May 2021

Cited by 14 | Viewed by 5069

Abstract

There has been a recent increase in the development of delivery systems based on red blood cells (RBCs) for light-mediated imaging and therapeutic applications. These constructs are able to take advantage of the immune evasion properties of the RBC, while the addition of [...] Read more.

There has been a recent increase in the development of delivery systems based on red blood cells (RBCs) for light-mediated imaging and therapeutic applications. These constructs are able to take advantage of the immune evasion properties of the RBC, while the addition of an optical cargo allows the particles to be activated by light for a number of promising applications. Here, we review some of the common fabrication methods to engineer these constructs. We also present some of the current light-based applications with potential for clinical translation, and offer some insight into future directions in this exciting field. Full article

(This article belongs to the Special Issue Bioinspired and Biomimicking Materials for Biomedical Applications)

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20 pages, 1093 KiB

Open AccessEditor’s ChoiceReview

The Pentose Phosphate Pathway in Yeasts–More Than a Poor Cousin of Glycolysis

by Laura-Katharina Bertels, Lucía Fernández Murillo and Jürgen J. Heinisch

Biomolecules 2021, 11(5), 725; https://doi.org/10.3390/biom11050725 - 12 May 2021

Cited by 76 | Viewed by 16458

Abstract

The pentose phosphate pathway (PPP) is a route that can work in parallel to glycolysis in glucose degradation in most living cells. It has a unidirectional oxidative part with glucose-6-phosphate dehydrogenase as a key enzyme generating NADPH, and a non-oxidative part involving the [...] Read more.

The pentose phosphate pathway (PPP) is a route that can work in parallel to glycolysis in glucose degradation in most living cells. It has a unidirectional oxidative part with glucose-6-phosphate dehydrogenase as a key enzyme generating NADPH, and a non-oxidative part involving the reversible transketolase and transaldolase reactions, which interchange PPP metabolites with glycolysis. While the oxidative branch is vital to cope with oxidative stress, the non-oxidative branch provides precursors for the synthesis of nucleic, fatty and aromatic amino acids. For glucose catabolism in the baker’s yeast Saccharomyces cerevisiae, where its components were first discovered and extensively studied, the PPP plays only a minor role. In contrast, PPP and glycolysis contribute almost equally to glucose degradation in other yeasts. We here summarize the data available for the PPP enzymes focusing on S. cerevisiae and Kluyveromyces lactis, and describe the phenotypes of gene deletions and the benefits of their overproduction and modification. Reference to other yeasts and to the importance of the PPP in their biotechnological and medical applications is briefly being included. We propose future studies on the PPP in K. lactis to be of special interest for basic science and as a host for the expression of human disease genes. Full article

(This article belongs to the Special Issue Fungal Metabolism - Enzymes and Bioactive Compounds)

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18 pages, 1997 KiB

Open AccessFeature PaperEditor’s ChoiceReview

Regulation of Tissue Inflammation by 12-Lipoxygenases

by Abhishek Kulkarni, Jerry L. Nadler, Raghavendra G. Mirmira and Isabel Casimiro

Biomolecules 2021, 11(5), 717; https://doi.org/10.3390/biom11050717 - 11 May 2021

Cited by 64 | Viewed by 8387

Abstract

Lipoxygenases (LOXs) are lipid metabolizing enzymes that catalyze the di-oxygenation of polyunsaturated fatty acids to generate active eicosanoid products. 12-lipoxygenases (12-LOXs) primarily oxygenate the 12th carbon of its substrates. Many studies have demonstrated that 12-LOXs and their eicosanoid metabolite 12-hydroxyeicosatetraenoate (12-HETE), have significant [...] Read more.

Lipoxygenases (LOXs) are lipid metabolizing enzymes that catalyze the di-oxygenation of polyunsaturated fatty acids to generate active eicosanoid products. 12-lipoxygenases (12-LOXs) primarily oxygenate the 12th carbon of its substrates. Many studies have demonstrated that 12-LOXs and their eicosanoid metabolite 12-hydroxyeicosatetraenoate (12-HETE), have significant pathological implications in inflammatory diseases. Increased level of 12-LOX activity promotes stress (both oxidative and endoplasmic reticulum)-mediated inflammation, leading to damage in these tissues. 12-LOXs are also associated with enhanced cellular migration of immune cells—a characteristic of several metabolic and autoimmune disorders. Genetic depletion or pharmacological inhibition of the enzyme in animal models of various diseases has shown to be protective against disease development and/or progression in animal models in the setting of diabetes, pulmonary, cardiovascular, and metabolic disease, suggesting a translational potential of targeting the enzyme for the treatment of several disorders. In this article, we review the role of 12-LOXs in the pathogenesis of several diseases in which chronic inflammation plays an underlying role. Full article

(This article belongs to the Collection Bioactive Lipids in Inflammation, Diabetes and Cancer)

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13 pages, 1339 KiB

Open AccessEditor’s ChoiceArticle

VEGF Mediates Retinal Müller Cell Viability and Neuroprotection through BDNF in Diabetes

by Yun-Zheng Le, Bei Xu, Ana J. Chucair-Elliott, Huiru Zhang and Meili Zhu

Biomolecules 2021, 11(5), 712; https://doi.org/10.3390/biom11050712 - 10 May 2021

Cited by 24 | Viewed by 4028

Abstract

To investigate the mechanism of vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) in Müller cell (MC) viability and neuroprotection in diabetic retinopathy (DR), we examined the role of VEGF in MC viability and BDNF production, and the effect of BDNF [...] Read more.

To investigate the mechanism of vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) in Müller cell (MC) viability and neuroprotection in diabetic retinopathy (DR), we examined the role of VEGF in MC viability and BDNF production, and the effect of BDNF on MC viability under diabetic conditions. Mouse primary MCs and cells of a rat MC line, rMC1, were used in investigating MC viability and BDNF production under diabetic conditions. VEGF-stimulated BDNF production was confirmed in mice. The mechanism of BDNF-mediated MC viability was examined using siRNA knockdown. Under diabetic conditions, recombinant VEGF (rVEGF) stimulated MC viability and BDNF production in a dose-dependent manner. rBDNF also supported MC viability in a dose-dependent manner. Targeting BDNF receptor tropomyosin receptor kinase B (TRK-B) with siRNA knockdown substantially downregulated the activated (phosphorylated) form of serine/threonine-specific protein kinase (AKT) and extracellular signal-regulated kinase (ERK), classical survival and proliferation mediators. Finally, the loss of MC viability in TrkB siRNA transfected cells under diabetic conditions was rescued by rBDNF. Our results provide direct evidence that VEGF is a positive regulator for BDNF production in diabetes for the first time. This information is essential for developing BDNF-mediated neuroprotection in DR and hypoxic retinal diseases, and for improving anti-VEGF treatment for these blood–retina barrier disorders, in which VEGF is a major therapeutic target for vascular abnormalities. Full article

(This article belongs to the Special Issue Ocular Diseases and Therapeutics)

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16 pages, 1491 KiB

Open AccessEditor’s ChoiceReview

Salicylic Acid Biosynthesis and Metabolism: A Divergent Pathway for Plants and Bacteria

by Awdhesh Kumar Mishra and Kwang-Hyun Baek

Biomolecules 2021, 11(5), 705; https://doi.org/10.3390/biom11050705 - 9 May 2021

Cited by 96 | Viewed by 18558

Abstract

Salicylic acid (SA) is an active secondary metabolite that occurs in bacteria, fungi, and plants. SA and its derivatives (collectively called salicylates) are synthesized from chorismate (derived from shikimate pathway). SA is considered an important phytohormone that regulates various aspects of plant growth, [...] Read more.

Salicylic acid (SA) is an active secondary metabolite that occurs in bacteria, fungi, and plants. SA and its derivatives (collectively called salicylates) are synthesized from chorismate (derived from shikimate pathway). SA is considered an important phytohormone that regulates various aspects of plant growth, environmental stress, and defense responses against pathogens. Besides plants, a large number of bacterial species, such as Pseudomonas, Bacillus, Azospirillum, Salmonella, Achromobacter, Vibrio, Yersinia, and Mycobacteria, have been reported to synthesize salicylates through the NRPS/PKS biosynthetic gene clusters. This bacterial salicylate production is often linked to the biosynthesis of small ferric-ion-chelating molecules, salicyl-derived siderophores (known as catecholate) under iron-limited conditions. Although bacteria possess entirely different biosynthetic pathways from plants, they share one common biosynthetic enzyme, isochorismate synthase, which converts chorismate to isochorismate, a common precursor for synthesizing SA. Additionally, SA in plants and bacteria can undergo several modifications to carry out their specific functions. In this review, we will systematically focus on the plant and bacterial salicylate biosynthesis and its metabolism. Full article

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23 pages, 1302 KiB

Open AccessEditor’s ChoiceReview

Biostimulants Application: A Low Input Cropping Management Tool for Sustainable Farming of Vegetables

by Mohamad Hesam Shahrajabian, Christina Chaski, Nikolaos Polyzos and Spyridon A. Petropoulos

Biomolecules 2021, 11(5), 698; https://doi.org/10.3390/biom11050698 - 7 May 2021

Cited by 126 | Viewed by 13418

Abstract

Biostimulants, are a diverse class of compounds including substances or microorganism which have positive impacts on plant growth, yield and chemical composition as well as boosting effects to biotic and abiotic stress tolerance. The major plant biostimulants are hydrolysates of plant or animal [...] Read more.

Biostimulants, are a diverse class of compounds including substances or microorganism which have positive impacts on plant growth, yield and chemical composition as well as boosting effects to biotic and abiotic stress tolerance. The major plant biostimulants are hydrolysates of plant or animal protein and other compounds that contain nitrogen, humic substances, extracts of seaweeds, biopolymers, compounds of microbial origin, phosphite, and silicon, among others. The mechanisms involved in the protective effects of biostimulants are varied depending on the compound and/or crop and mostly related with improved physiological processes and plant morphology aspects such as the enhanced root formation and elongation, increased nutrient uptake, improvement in seed germination rates and better crop establishment, increased cation exchange, decreased leaching, detoxification of heavy metals, mechanisms involved in stomatal conductance and plant transpiration or the stimulation of plant immune systems against stressors. The aim of this review was to provide an overview of the application of plant biostimulants on different crops within the framework of sustainable crop management, aiming to gather critical information regarding their positive effects on plant growth and yield, as well as on the quality of the final product. Moreover, the main limitations of such practice as well as the future prospects of biostimulants research will be presented. Full article

(This article belongs to the Special Issue Recent Advances and Applications of Biostimulants for Plant Growth Promotion and Environmental Stress Adaptation)

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34 pages, 21908 KiB

Open AccessEditor’s ChoiceReview

SARS-CoV-2 M^pro: A Potential Target for Peptidomimetics and Small-Molecule Inhibitors

by Andrea Citarella, Angela Scala, Anna Piperno and Nicola Micale

Biomolecules 2021, 11(4), 607; https://doi.org/10.3390/biom11040607 - 19 Apr 2021

Cited by 137 | Viewed by 13499

Abstract

The uncontrolled spread of the COVID-19 pandemic caused by the new coronavirus SARS-CoV-2 during 2020–2021 is one of the most devastating events in the history, with remarkable impacts on the health, economic systems, and habits of the entire world population. While some effective [...] Read more.

The uncontrolled spread of the COVID-19 pandemic caused by the new coronavirus SARS-CoV-2 during 2020–2021 is one of the most devastating events in the history, with remarkable impacts on the health, economic systems, and habits of the entire world population. While some effective vaccines are nowadays approved and extensively administered, the long-term efficacy and safety of this line of intervention is constantly under debate as coronaviruses rapidly mutate and several SARS-CoV-2 variants have been already identified worldwide. Then, the WHO’s main recommendations to prevent severe clinical complications by COVID-19 are still essentially based on social distancing and limitation of human interactions, therefore the identification of new target-based drugs became a priority. Several strategies have been proposed to counteract such viral infection, including the repurposing of FDA already approved for the treatment of HIV, HCV, and EBOLA, inter alia. Among the evaluated compounds, inhibitors of the main protease of the coronavirus (M^pro) are becoming more and more promising candidates. M^pro holds a pivotal role during the onset of the infection and its function is intimately related with the beginning of viral replication. The interruption of its catalytic activity could represent a relevant strategy for the development of anti-coronavirus drugs. SARS-CoV-2 M^pro is a peculiar cysteine protease of the coronavirus family, responsible for the replication and infectivity of the parasite. This review offers a detailed analysis of the repurposed drugs and the newly synthesized molecules developed to date for the treatment of COVID-19 which share the common feature of targeting SARS-CoV-2 M^pro, as well as a brief overview of the main enzymatic and cell-based assays to efficaciously screen such compounds. Full article

(This article belongs to the Special Issue State-of-the-Art Highlighting Antiviral Therapy and Viral Diseases Diagnosis in Italy 2020–2021)

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35 pages, 3533 KiB

Open AccessEditor’s ChoiceReview

A Comprehensive Review of Cholinesterase Modeling and Simulation

by Danna De Boer, Nguyet Nguyen, Jia Mao, Jessica Moore and Eric J. Sorin

Biomolecules 2021, 11(4), 580; https://doi.org/10.3390/biom11040580 - 15 Apr 2021

Cited by 66 | Viewed by 11566

Abstract

The present article reviews published efforts to study acetylcholinesterase and butyrylcholinesterase structure and function using computer-based modeling and simulation techniques. Structures and models of both enzymes from various organisms, including rays, mice, and humans, are discussed to highlight key structural similarities in the [...] Read more.

The present article reviews published efforts to study acetylcholinesterase and butyrylcholinesterase structure and function using computer-based modeling and simulation techniques. Structures and models of both enzymes from various organisms, including rays, mice, and humans, are discussed to highlight key structural similarities in the active site gorges of the two enzymes, such as flexibility, binding site location, and function, as well as differences, such as gorge volume and binding site residue composition. Catalytic studies are also described, with an emphasis on the mechanism of acetylcholine hydrolysis by each enzyme and novel mutants that increase catalytic efficiency. The inhibitory activities of myriad compounds have been computationally assessed, primarily through Monte Carlo-based docking calculations and molecular dynamics simulations. Pharmaceutical compounds examined herein include FDA-approved therapeutics and their derivatives, as well as several other prescription drug derivatives. Cholinesterase interactions with both narcotics and organophosphate compounds are discussed, with the latter focusing primarily on molecular recognition studies of potential therapeutic value and on improving our understanding of the reactivation of cholinesterases that are bound to toxins. This review also explores the inhibitory properties of several other organic and biological moieties, as well as advancements in virtual screening methodologies with respect to these enzymes. Full article

(This article belongs to the Special Issue Cholinesterase Research)

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21 pages, 5191 KiB

Open AccessEditor’s ChoiceArticle

Liquid–Liquid Phase Separation Enhances TDP-43 LCD Aggregation but Delays Seeded Aggregation

by Donya Pakravan, Emiel Michiels, Anna Bratek-Skicki, Mathias De Decker, Joris Van Lindt, David Alsteens, Sylvie Derclaye, Philip Van Damme, Joost Schymkowitz, Frederic Rousseau, Peter Tompa and Ludo Van Den Bosch

Biomolecules 2021, 11(4), 548; https://doi.org/10.3390/biom11040548 - 8 Apr 2021

Cited by 32 | Viewed by 8519

Abstract

Aggregates of TAR DNA-binding protein (TDP-43) are a hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although TDP-43 aggregates are an undisputed pathological species at the end stage of these diseases, the molecular changes underlying the initiation of aggregation are not [...] Read more.

Aggregates of TAR DNA-binding protein (TDP-43) are a hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although TDP-43 aggregates are an undisputed pathological species at the end stage of these diseases, the molecular changes underlying the initiation of aggregation are not fully understood. The aim of this study was to investigate how phase separation affects self-aggregation and aggregation seeded by pre-formed aggregates of either the low-complexity domain (LCD) or its short aggregation-promoting regions (APRs). By systematically varying the physicochemical conditions, we observed that liquid–liquid phase separation (LLPS) promotes spontaneous aggregation. However, we noticed less efficient seeded aggregation in phase separating conditions. By analyzing a broad range of conditions using the Hofmeister series of buffers, we confirmed that stabilizing hydrophobic interactions prevail over destabilizing electrostatic forces. RNA affected the cooperativity between LLPS and aggregation in a “reentrant” fashion, having the strongest positive effect at intermediate concentrations. Altogether, we conclude that conditions which favor LLPS enhance the subsequent aggregation of the TDP-43 LCD with complex dependence, but also negatively affect seeding kinetics. Full article

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27 pages, 12234 KiB

Open AccessEditor’s ChoiceReview

The 40-Year Mystery of Insect Odorant-Binding Proteins

by Karen Rihani, Jean-François Ferveur and Loïc Briand

Biomolecules 2021, 11(4), 509; https://doi.org/10.3390/biom11040509 - 30 Mar 2021

Cited by 131 | Viewed by 10490

Abstract

The survival of insects depends on their ability to detect molecules present in their environment. Odorant-binding proteins (OBPs) form a family of proteins involved in chemoreception. While OBPs were initially found in olfactory appendages, recently these proteins were discovered in other chemosensory and [...] Read more.

The survival of insects depends on their ability to detect molecules present in their environment. Odorant-binding proteins (OBPs) form a family of proteins involved in chemoreception. While OBPs were initially found in olfactory appendages, recently these proteins were discovered in other chemosensory and non-chemosensory organs. OBPs can bind, solubilize and transport hydrophobic stimuli to chemoreceptors across the aqueous sensilla lymph. In addition to this broadly accepted “transporter role”, OBPs can also buffer sudden changes in odorant levels and are involved in hygro-reception. The physiological roles of OBPs expressed in other body tissues, such as mouthparts, pheromone glands, reproductive organs, digestive tract and venom glands, remain to be investigated. This review provides an updated panorama on the varied structural aspects, binding properties, tissue expression and functional roles of insect OBPs. Full article

(This article belongs to the Special Issue Insect Receptors: Biochemical, Physiological and Molecular Studies)

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14 pages, 318 KiB

Open AccessEditor’s ChoiceReview

Current Status and Future Perspectives of Androgen Receptor Inhibition Therapy for Prostate Cancer: A Comprehensive Review

by Tae Jin Kim, Young Hwa Lee and Kyo Chul Koo

Biomolecules 2021, 11(4), 492; https://doi.org/10.3390/biom11040492 - 25 Mar 2021

Cited by 34 | Viewed by 5438

Abstract

The androgen receptor (AR) is one of the main components in the development and progression of prostate cancer (PCa), and treatment strategies are mostly directed toward manipulation of the AR pathway. In the metastatic setting, androgen deprivation therapy (ADT) is the foundation of [...] Read more.

The androgen receptor (AR) is one of the main components in the development and progression of prostate cancer (PCa), and treatment strategies are mostly directed toward manipulation of the AR pathway. In the metastatic setting, androgen deprivation therapy (ADT) is the foundation of treatment in patients with hormone-sensitive prostate cancer (HSPC). However, treatment response is short-lived, and the majority of patients ultimately progress to castration-resistant prostate cancer (CRPC). Surmountable data from clinical trials have shown that the maintenance of AR signaling in the castration environment is accountable for disease progression. Study results indicate multiple factors and survival pathways involved in PCa. Based on these findings, the alternative molecular pathways involved in PCa progression can be manipulated to improve current regimens and develop novel treatment modalities in the management of CRPC. In this review, the interaction between AR signaling and other molecular pathways involved in tumor pathogenesis and its clinical implications in metastasis and advanced disease will be discussed, along with a thorough overview of current and ongoing novel treatments for AR signaling inhibition. Full article

(This article belongs to the Special Issue Androgen Receptors in Health and Diseases)

17 pages, 2273 KiB

Open AccessEditor’s ChoiceReview

Antiviral Cyanometabolites—A Review

by Hanna Mazur-Marzec, Marta Cegłowska, Robert Konkel and Krzysztof Pyrć

Biomolecules 2021, 11(3), 474; https://doi.org/10.3390/biom11030474 - 22 Mar 2021

Cited by 42 | Viewed by 6512

Abstract

Global processes, such as climate change, frequent and distant travelling and population growth, increase the risk of viral infection spread. Unfortunately, the number of effective and accessible medicines for the prevention and treatment of these infections is limited. Therefore, in recent years, efforts [...] Read more.

Global processes, such as climate change, frequent and distant travelling and population growth, increase the risk of viral infection spread. Unfortunately, the number of effective and accessible medicines for the prevention and treatment of these infections is limited. Therefore, in recent years, efforts have been intensified to develop new antiviral medicines or vaccines. In this review article, the structure and activity of the most promising antiviral cyanobacterial products are presented. The antiviral cyanometabolites are mainly active against the human immunodeficiency virus (HIV) and other enveloped viruses such as herpes simplex virus (HSV), Ebola or the influenza viruses. The majority of the metabolites are classified as lectins, monomeric or dimeric proteins with unique amino acid sequences. They all show activity at the nanomolar range but differ in carbohydrate specificity and recognize a different epitope on high mannose oligosaccharides. The cyanobacterial lectins include cyanovirin-N (CV-N), scytovirin (SVN), microvirin (MVN), Microcystisviridis lectin (MVL), and Oscillatoria agardhii agglutinin (OAA). Cyanobacterial polysaccharides, peptides, and other metabolites also have potential to be used as antiviral drugs. The sulfated polysaccharide, calcium spirulan (CA-SP), inhibited infection by enveloped viruses, stimulated the immune system’s response, and showed antitumor activity. Microginins, the linear peptides, inhibit angiotensin-converting enzyme (ACE), therefore, their use in the treatment of COVID-19 patients with injury of the ACE2 expressing organs is considered. In addition, many cyanobacterial extracts were revealed to have antiviral activities, but the active agents have not been identified. This fact provides a good basis for further studies on the therapeutic potential of these microorganisms. Full article

(This article belongs to the Special Issue Biomolecules from Alga: Biological Effect and Pharmacological Properties)

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29 pages, 12461 KiB

Open AccessEditor’s ChoiceReview

Neuropathology of Animal Prion Diseases

by Leonor Orge, Carla Lima, Carla Machado, Paula Tavares, Paula Mendonça, Paulo Carvalho, João Silva, Maria de Lurdes Pinto, Estela Bastos, Jorge Cláudio Pereira, Nuno Gonçalves-Anjo, Adelina Gama, Alexandra Esteves, Anabela Alves, Ana Cristina Matos, Fernanda Seixas, Filipe Silva, Isabel Pires, Luis Figueira, Madalena Vieira-Pinto, Roberto Sargo and Maria dos Anjos Pires Show full author list Hide full author list

Biomolecules 2021, 11(3), 466; https://doi.org/10.3390/biom11030466 - 21 Mar 2021

Cited by 31 | Viewed by 8253

Abstract

Transmissible Spongiform Encephalopathies (TSEs) or prion diseases are a fatal group of infectious, inherited and spontaneous neurodegenerative diseases affecting human and animals. They are caused by the conversion of cellular prion protein (PrP^C) into a misfolded pathological isoform (PrP^Sc or [...] Read more.

Transmissible Spongiform Encephalopathies (TSEs) or prion diseases are a fatal group of infectious, inherited and spontaneous neurodegenerative diseases affecting human and animals. They are caused by the conversion of cellular prion protein (PrP^C) into a misfolded pathological isoform (PrP^Sc or prion- proteinaceous infectious particle) that self-propagates by conformational conversion of PrP^C. Yet by an unknown mechanism, PrP^C can fold into different PrP^Sc conformers that may result in different prion strains that display specific disease phenotype (incubation time, clinical signs and lesion profile). Although the pathways for neurodegeneration as well as the involvement of brain inflammation in these diseases are not well understood, the spongiform changes, neuronal loss, gliosis and accumulation of PrP^Sc are the characteristic neuropathological lesions. Scrapie affecting small ruminants was the first identified TSE and has been considered the archetype of prion diseases, though atypical and new animal prion diseases continue to emerge highlighting the importance to investigate the lesion profile in naturally affected animals. In this report, we review the neuropathology and the neuroinflammation of animal prion diseases in natural hosts from scrapie, going through the zoonotic bovine spongiform encephalopathy (BSE), the chronic wasting disease (CWD) to the newly identified camel prion disease (CPD). Full article

(This article belongs to the Special Issue Prion Diseases: A Natural Model for Neurodegenerative Disorders)

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37 pages, 4133 KiB

Open AccessEditor’s ChoiceReview

New Avenues for Parkinson’s Disease Therapeutics: Disease-Modifying Strategies Based on the Gut Microbiota

by Marina Lorente-Picón and Ariadna Laguna

Biomolecules 2021, 11(3), 433; https://doi.org/10.3390/biom11030433 - 15 Mar 2021

Cited by 49 | Viewed by 12869

Abstract

Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder that currently affects 1% of the population over the age of 60 years, and for which no disease-modifying treatments exist. Neurodegeneration and neuropathology in different brain areas are manifested as both motor and non-motor symptoms [...] Read more.

Parkinson’s disease (PD) is a multifactorial neurodegenerative disorder that currently affects 1% of the population over the age of 60 years, and for which no disease-modifying treatments exist. Neurodegeneration and neuropathology in different brain areas are manifested as both motor and non-motor symptoms in patients. Recent interest in the gut–brain axis has led to increasing research into the gut microbiota changes in PD patients and their impact on disease pathophysiology. As evidence is piling up on the effects of gut microbiota in disease development and progression, another front of action has opened up in relation to the potential usage of microbiota-based therapeutic strategies in treating gastrointestinal alterations and possibly also motor symptoms in PD. This review provides status on the different strategies that are in the front line (i.e., antibiotics; probiotics; prebiotics; synbiotics; dietary interventions; fecal microbiota transplantation, live biotherapeutic products), and discusses the opportunities and challenges the field of microbiome research in PD is facing. Full article

(This article belongs to the Section Cellular Biochemistry)

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8 pages, 813 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

COVID-19 Rapid Antigen Test as Screening Strategy at Points of Entry: Experience in Lazio Region, Central Italy, August–October 2020

by Francesca Colavita, Francesco Vairo, Silvia Meschi, Maria Beatrice Valli, Eleonora Lalle, Concetta Castilletti, Danilo Fusco, Giuseppe Spiga, Pierluigi Bartoletti, Simona Ursino, Maurizio Sanguinetti, Antonino Di Caro, Francesco Vaia, Giuseppe Ippolito and Maria Rosaria Capobianchi

Biomolecules 2021, 11(3), 425; https://doi.org/10.3390/biom11030425 - 13 Mar 2021

Cited by 21 | Viewed by 5217

Abstract

COVID-19 pandemic is a dramatic health, social and economic global challenge. There is urgent need to maximize testing capacity. Rapid Antigen Tests (RAT) represent good candidates for point-of-care and mass surveillance testing to rapidly identify SARS-CoV-2-infected people, counterbalancing lower sensitivity vs. gold standard [...] Read more.

COVID-19 pandemic is a dramatic health, social and economic global challenge. There is urgent need to maximize testing capacity. Rapid Antigen Tests (RAT) represent good candidates for point-of-care and mass surveillance testing to rapidly identify SARS-CoV-2-infected people, counterbalancing lower sensitivity vs. gold standard molecular tests with fast results and possible recurrent testing. We describe the results obtained with the testing algorithm implemented at points of entry (airports and ports) in the Lazio Region (Italy), using the STANDARD F COVID-19 Antigen Fluorescence ImmunoAssay (FIA), followed by molecular confirmation of FIA-positive samples. From mid-August to mid-October 2020, 73,643 RAT were reported to the Regional Surveillance Information System for travelers at points of entry in Lazio Region. Of these, 1176 (1.6%) were FIA-positive, and the proportion of RT-PCR-confirmed samples was 40.5%. Our data show that the probability of confirmation was directly dependent from the semi-quantitative FIA results. In addition, the molecularly confirmed samples were those with high levels of virus and that were actually harboring infectious virus. These results support public health strategies based on early mass screening campaigns by RAT in settings where molecular testing is not feasible or easily accessible, such as points of entry. This approach would contribute to promptly controlling viral spread through travel, which is now of particular concern due to the spread of SARS-CoV-2 variants. Full article

(This article belongs to the Special Issue State-of-the-Art Highlighting Antiviral Therapy and Viral Diseases Diagnosis in Italy 2020–2021)

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20 pages, 3844 KiB

Open AccessEditor’s ChoiceReview

RAS Nanoclusters: Dynamic Signaling Platforms Amenable to Therapeutic Intervention

by Que N. Van, Priyanka Prakash, Rebika Shrestha, Trent E. Balius, Thomas J. Turbyville and Andrew G. Stephen

Biomolecules 2021, 11(3), 377; https://doi.org/10.3390/biom11030377 - 3 Mar 2021

Cited by 22 | Viewed by 5074

Abstract

RAS proteins are mutated in approximately 20% of all cancers and are generally associated with poor clinical outcomes. RAS proteins are localized to the plasma membrane and function as molecular switches, turned on by partners that receive extracellular mitogenic signals. In the on-state, [...] Read more.

RAS proteins are mutated in approximately 20% of all cancers and are generally associated with poor clinical outcomes. RAS proteins are localized to the plasma membrane and function as molecular switches, turned on by partners that receive extracellular mitogenic signals. In the on-state, they activate intracellular signal transduction cascades. Membrane-bound RAS molecules segregate into multimers, known as nanoclusters. These nanoclusters, held together through weak protein–protein and protein–lipid associations, are highly dynamic and respond to cellular input signals and fluctuations in the local lipid environment. Disruption of RAS nanoclusters results in downregulation of RAS-mediated mitogenic signaling. In this review, we discuss the propensity of RAS proteins to display clustering behavior and the interfaces that are associated with these assemblies. Strategies to therapeutically disrupt nanocluster formation or the stabilization of signaling incompetent RAS complexes are discussed. Full article

(This article belongs to the Special Issue Recent Insights into the Regulation and Structure of RAS Membrane Signaling Complexes—Emerging Drug Targeting Opportunities)

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31 pages, 2324 KiB

Open AccessEditor’s ChoiceReview

by Jason Tallis, Sharn Shelley, Hans Degens and Cameron Hill

Biomolecules 2021, 11(3), 372; https://doi.org/10.3390/biom11030372 - 2 Mar 2021

Cited by 27 | Viewed by 8658

Abstract

Obesity is a global epidemic and coupled with the unprecedented growth of the world’s older adult population, a growing number of individuals are both old and obese. Whilst both ageing and obesity are associated with an increased prevalence of chronic health conditions and [...] Read more.

Obesity is a global epidemic and coupled with the unprecedented growth of the world’s older adult population, a growing number of individuals are both old and obese. Whilst both ageing and obesity are associated with an increased prevalence of chronic health conditions and a substantial economic burden, evidence suggests that the coincident effects exacerbate negative health outcomes. A significant contributor to such detrimental effects may be the reduction in the contractile performance of skeletal muscle, given that poor muscle function is related to chronic disease, poor quality of life and all-cause mortality. Whilst the effects of ageing and obesity independently on skeletal muscle function have been investigated, the combined effects are yet to be thoroughly explored. Given the importance of skeletal muscle to whole-body health and physical function, the present study sought to provide a review of the literature to: (1) summarise the effect of obesity on the age-induced reduction in skeletal muscle contractile function; (2) understand whether obesity effects on skeletal muscle are similar in young and old muscle; (3) consider the consequences of these changes to whole-body functional performance; (4) outline important future work along with the potential for targeted intervention strategies to mitigate potential detrimental effects. Full article

(This article belongs to the Special Issue The Molecular and Physiological Mechanisms Responsible for The Interaction between Aging, Muscle, and Other Tissues)

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17 pages, 1314 KiB

Open AccessEditor’s ChoiceArticle

Rapamycin Improves Recognition Memory and Normalizes Amino-Acids and Amines Levels in the Hippocampal Dentate Gyrus in Adult Rats Exposed to Ethanol during the Neonatal Period

by Malgorzata Lopatynska-Mazurek, Anna Pankowska, Ewa Gibula-Tarlowska, Radoslaw Pietura and Jolanta H. Kotlinska

Biomolecules 2021, 11(3), 362; https://doi.org/10.3390/biom11030362 - 27 Feb 2021

Cited by 13 | Viewed by 3282

Abstract

The mammalian target of rapamycin (mTOR), a serine/ threonine kinase, is implicated in synaptic plasticity by controlling protein synthesis. Research suggests that ethanol exposure during pregnancy alters the mTOR signaling pathway in the fetal hippocampus. Thus, we investigated the influence of pre-treatment with [...] Read more.

The mammalian target of rapamycin (mTOR), a serine/ threonine kinase, is implicated in synaptic plasticity by controlling protein synthesis. Research suggests that ethanol exposure during pregnancy alters the mTOR signaling pathway in the fetal hippocampus. Thus, we investigated the influence of pre-treatment with rapamycin, an mTORC1 inhibitor, on the development of recognition memory deficits in adult rats that were neonatally exposed to ethanol. In the study, male and female rat pups received ethanol (5 g/kg/day) by intragastric intubation at postanatal day (PND 4-9), an equivalent to the third trimester of human pregnancy. Rapamycin (3 and 10 mg/kg) was given intraperitoneally before every ethanol administration. Short- and long-term recognition memory was assessed in the novel object recognition (NOR) task in adult (PND 59/60) rats. Locomotor activity and anxiety-like behavior were also evaluated to exclude the influence of such behavior on the outcome of the memory task. Moreover, the effects of rapamycin pre-treatment during neonatal ethanol exposure on the content of amino-acids and amines essential for the proper development of cognitive function in the dentate gyrus (DG) of the hippocampus was evaluated using proton magnetic resonance spectroscopy (1H MRS) in male adult (PND 60) rats. Our results show the deleterious effect of ethanol given to neonatal rats on long-term recognition memory in adults. The effect was more pronounced in male rather than female rats. Rapamycin reversed this ethanol-induced memory impairment and normalized the levels of amino acids and amines in the DG. This suggests the involvement of mTORC1 in the deleterious effect of ethanol on the developing brain. Full article

(This article belongs to the Collection TOR Signaling Pathway)

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